This invention relates to novel analogs of swainsonine, processes for the preparation of these analogs, and their use as therapeutic agents.
The xcex1-mannosidase inhibitor swainsonine (1) continues to be the most promising anti-cancer agent among the polyhydroxylated alkaloids. Swainsonine inhibits the metastasis and growth rate of a number of human tumors in murine models,1 and has entered clinical trials in humans. Swainsonine appears to exhibit its anti-cancer activity in a variety of ways. Swainsonine""s anti-metastatic activity is associated with its ability to reduce tumor cell adhesion to the endothelium,2,3 as well as its ability to inhibit tumor cell invasion through the extracellular matrix.4-6 The anti-cancer activity of swainsonine is also associated with its ability to stimulate the immune system of the host. Swainsonine activates the natural killer cells (NK cells) that participate in the elimination of blood-borne B16-F10 melanoma cells,7 and enhances lymphocyte activate killer cell (LAK cell) activity against human colon carcinoma cells in an interleukin-2 mediated fashion.8 Further, swainsonine protects the host immune system against immunosuppressive proteins produced by tumors,9 and stimulates bone marrow proliferation in the presence of cytotoxic anti-cancer drugs such as methotrexate, 5-fluorouracil, cyclophosphamide and doxorubicin.10 
The therapeutic activities of swainsonine are generally attributed to its ability to inhibit the Golgi glycoprotein processing enzyme mannosidase II. Inhibition of this enzyme allows for the formation of high-mannose and hybrid type glycoprotein oligosaccharides but prevents the formation of complex-type oligosaccharides. Since swainsonine inhibits glycoprotein processing at a relatively late stage in the pathway, it generally does not block membrane localization or secretion of glycoproteins, and thus shows less toxicity than glycoprotein inhibitors that act earlier in the pathway.
Swainsonine showed low preclinical toxicity in animals11,12 and has entered Phase I clinical trials in humans. Initial results of these trials were reported recently.13-15 Swainsonine was administered to 19 patients with advanced malignancies at levels of 50 to 550 xcexcg/kg/day by continuous i.v. infusion over 5 days, repeated at 28 day intervals. Moderate toxicity was observed, with common side effects including edema, mild liver and pancreas dysfunction, increased serum amylase levels, and decreased serum retinol levels. Serum half-life was determined to be 0.5 days with a clearance rate of 2 mL/hxe2x80xa2kg. Both Golgi xcex1-mannosidase II and tissue lysosomal xcex1-mannosidases were inhibited. Inhibition of the lysosomal xcex1-mannosidase resulted in accumulation of oligomannosides observable by analysis of the urine. One possible treatment related death was reported, and at least three patients showed improvement over the course of treatment. Clinical trials studying chronic oral administration of swainsonine are currently in progress.
The present inventors report the preparation of swainsonine analogs such as 2, 3, and 4 shown below. Ring substitution at the 6- and 7-positions was found to afford increased selectivity for these analogs, in the following sense. The therapeutic activity of swainsonine is associated with its ability to inhibit the Golgi glycoprotein processing enzyme xcex1-mannosidase II. However, swainsonine also inhibits the lysosomal 
mannosidase that it responsible for the catabolic degradation of oligosaccharide chains. Inhibition of this enzyme leads to the accumulation of carbohydrates is tissues, a condition known as lysosomal storage, that is an unwanted side effect associated with the use of swainsonine as a therapeutic agent.1 Unfortunately, swainsonine is more effective at inhibiting the lysosomal mannosidase (undesired) than the Golgi mannosidase (desired). An inhibitor that could discriminate between the glycoprotein processing and the lysosomal mannosidases would have clear advantages as a potential drug. Incorporation of substituents on swainsonine at C(6) and C(7), reported herein, affords the first swainsonine analogs with the ability to selectively inhibit xcex1-mannosidase II rather than lysosomal mannosidase, a crucial selectivity for the advancement of these types of compounds for cancer chemotherapy.1 
The present invention therefore relates to compounds with the formula I, 
wherein X and Y may be any combination of the following groups, except that X and Y cannot both be hydrogen:
H (when the other group is not H)
CH3 
(CH2)nCH3, where n=1-11
s-alkyl
(CH2)nxe2x80x94G, where G is branched alkyl, n=1-11
(CH2)nxe2x80x94Ar, where n=1-11; Ar=aryl, e.g. phenyl, substituted phenyl, naphthyl, substituted naphthyl, heteroaryl (e.g. pyridine, pyrimidine, pyrazine, triazine, furan, thiophene pyrrole, pyrazole, imidazole, triazole, thiazole, oxazole, isothiazole, isoxazole, and substituted versions thereof).
(CH2)nxe2x80x94FG, where n=1-11; FG=common functional groups or derivatized versions thereof (e.g. alkene, alkyne, substituted alkene, substituted alkyne, halide, alcohol, ether, amine, alkylated amine, carboxylic acid, carboxylic ester, acylated alcohol, acylated amine, sulfonamide, sulfide, thiol, sulfone, sulfoxide, sulfonated amine, azide, aldehyde, ketone, oxime, hydrazone, etc.)
CH(OH)R4, where R4=CH3, n-alkyl, s-alkyl, (CH2)nxe2x80x94G, (CH2)nxe2x80x94Ar, (CH2)nxe2x80x94FG (see above for definitions of G, Ar, and FG)
C(OH)R4R5, where R4 and/or R5=CH3, n-alkyl, s-alkyl, (CH2)nxe2x80x94G, (C2)nxe2x80x94Ar, (CH2)nxe2x80x94FG (see above for definitions of G, Ar, and FG)
R4xe2x80x94CO, where R4=CH3, n-alkyl, s-alkyl, (CH2)nxe2x80x94G, (CH2)nxe2x80x94Ar, (CH2)nxe2x80x94FG (see above for definitions of G, Ar, and FG), other ketone derivatives (e.g., oximes, hydrazones, etc.)
OH, OR, OCOR4 (see above for R4), other alcohol derivatives
N3, NH2, NHR4, NR4R5, NHCOR4, NR4COR5, NHSO2R4, NR4SO2R5, other amine derivatives PhS, PhS(O), PhSO2 
PhSe
Owing to the chirality of I, it can exist in racemic and optically active forms. It is understood that the present invention encompasses a compound of formula I as a mixture of diastereomers, as well as in the form of an individual diastereomer, and that the present invention encompasses a compound of formula I as a mixture of enantiomers, as well as in the form of an individual enantiomer.